WO2009029192A1 - Solution antimicrobienne à base de tensioactif, pour inhalation - Google Patents

Solution antimicrobienne à base de tensioactif, pour inhalation Download PDF

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WO2009029192A1
WO2009029192A1 PCT/US2008/009931 US2008009931W WO2009029192A1 WO 2009029192 A1 WO2009029192 A1 WO 2009029192A1 US 2008009931 W US2008009931 W US 2008009931W WO 2009029192 A1 WO2009029192 A1 WO 2009029192A1
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composition according
antimicrobial agent
aerosol
composition
surfactant
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WO2009029192A8 (fr
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Tim Corcoran
Amy Lise Marcinkowski
Joseph Pilewski
Kristina Thomas
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University Of Pittsburgh - Of The Commonwealth System Of Higher Education
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/65—Tetracyclines
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
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    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the present invention relates to a pharmaceutical composition for treating microbial infections in the body, specifically in the lung, and to a system for aerosol administration of the composition.
  • TOBI Tobramycin Solution for Inhalation
  • the TOBI regimen offers the advantages of (1) a specific dosage that studies have verified has an acceptable level of safety and effectiveness and (2) a recommended delivery system that provides adequate deposition of the drug solution to target sites in the lungs.
  • the TOBI regimen can achieve bacterial suppression, it does not eradicate infection fully. Over the course of clinical trials, for example, TOBI reduced bacterial density during administration but did not prevent a return of bacterial density to baseline levels, post- administration. Apparently failing to reach all bacterial reservoirs in the lungs, in other words, TOBI's aerosol particles did not eradicate the source of the infection.
  • a sterile, isotonic aqueous composition comprised of (i) an antimicrobial agent and (ii) a non-ionic surfactant in an amount such that nebulization of the composition yields an aerosol characterized by a median droplet size in the range of about 1 to 5 ⁇ m, which composition does not comprise phospholipids.
  • the composition has a surface tension of about 35 dynes/cm and, more preferably, of less than about 35 dynes (mN) per centimeter (cm).
  • the primary determinant of surface tension in this context is the surfactant, which preferably is tyloxapol, present in an amount that is less than about 1% by mass, e.g., about 0.1% by mass.
  • the antimicrobial agent may be an antibiotic, an antifungal, or an antiviral agent, or a combination of any of these.
  • suitable antimicrobial agents are: (A) tobramycin, amakacin, ceftazidime, aztreonam, colistin, ciprofloxacin, azithromycin, pentamidine, and gentamicin; (B) vancomycin, doxycycline, linezolid, meropenem, and tigecycline; (C) isoniazid, rifampin, and daptomycin; (D) Amphotericin B; and (E) zanamivir and oseltamivir.
  • the antimicrobial agent is tobramycin, present in an amount up to about 10% by mass.
  • a combination for delivering an antimicrobial agent to the lungs by oral inhalation, comprising (A) a breath- actuated nebulizer operatively connected to (B) a high-flow compressor that delivers to the nebulizer a gas flow greater than 5 L/min and a pressure head of at least 40 psi, where the nebulizer contains a liquid to be atomized that is an aqueous composition as described above.
  • the invention provides a method for delivering an antimicrobial agent to the lungs, comprising (A) forming an aerosol of such an aqueous composition, where said aerosol is characterized by a median droplet size in the range of about 1 to 5 ⁇ m, and (B) delivering that aerosol to a subject for inhalation, such that said subject receives aerosol only during inhalation.
  • FIGURES IA and IB provide a series of graphs that display the results of studies demonstrating a proportional relationship between tobramycin mass and radioactive counts when an SBTSI-Technetium DTPA solution was nebulized.
  • FIGURE 2 is a histogram that compares aerosol volume distribution for a SBTSI solution versus a tyloxapol-only solution of the same surfactant concentration.
  • FIGURE 3 is a graph that displays predicted total and pulmonary deposited tobramycin for each of the tested eleven delivery systems.
  • FIGURE 4 is a graphical depiction of the pulmonary delivery rate for each of eleven delivery systems.
  • FIGURE 5 is graph that shows the predicted delivery rate of medication to the large bronchial airways of the lungs.
  • FIGURE 6 is a graph depicting the predicted aerosol volume distribution by lung region for SBTSI used with a preferred nebulizer-compressor combination.
  • the use of a surfactant in an inhalation therapy causes the active agent or drug to disperse over a greater surface area of the target site, after aerosol deposition.
  • an aerosolized drug solution includes a significant surfactant concentration
  • Marangoni flows cause the drug particles, once deposited on the target site, to spread over a wider surface area.
  • surfactants have displayed an effective dispersing ability and have a good safety record for in vivo use, particularly in the lungs.
  • a pharmaceutical composition of the invention contains surfactant such that the surface tension of the composition, measured in conventional fashion, is about 35 mN/cm or less, the numerical value being approximately the surface tension of the endogenous liquid that lines the large airways of the human lung. See, e.g., Im Hof et al, Respir. Physiol. 109: 81-93 (1997), and Tarran et at., J. Gen. Physiol. 118: 223-36 (2001).
  • the lower end of the surface-tension range for the present invention is the lowest value measured heretofore in surfactant solutions delivered to the lungs for surfactant replacement therapy, which is on the order of 3 to 4 mN/cm.
  • surface tension of a composition can be measured via any suitable technique, of which a number are conventionally available.
  • any suitable technique of which a number are conventionally available.
  • PHYSICAL CHEMISTRY OF SURFACES 6 th ed. (John Wiley & Sons, Inc.), pages 16-33.
  • One such technique, the so-called "ring method” employs the de noisyiy ring system, in which a metallic ring of platinum and/or iridium is applied to measure surface tension. Id., pages 21-23. The ring forms an interface with the test liquid, and a tensiometer measures the tensile strength required to detach the ring from the liquid surface.
  • the de No ⁇ y ring system is versatile and suitable for approximating the surface tension of a composition with the present invention.
  • the formulation of Example 1 comprised of tobramycin (antibiotic) and tyloxapol (surfactant), was measured three time with a de No ⁇ y ring system, yielding values of 36.2, 37.2, and 37.2 dynes/cm. Accordingly, this method provided an average surface tension of 36.6 ⁇ 0.47 dynes/cm, which, for the applicable circumstances, was "about" 35 dyes/cm and operationally effective.
  • surface tension may be measured, as such, to inform pre-clinical development, pursuant to this invention, of a formulation that has a surface tension value that is "about" 35 dynes/cm or lower.
  • the chosen surfactant should not interfere with the medicinal properties of an administered composition that derives from the antimicrobial agent so employed.
  • the surfactant preferably is non-ionic; that is, it is uncharged and not prone to dissociate in water.
  • the employed antimicrobial agent includes but is not limited to a number of antibiotic, antifungal, and antiviral agents, as discussed in detail below.
  • a pharmaceutical composition of the invention should be aqueous and sterile, and should have essentially the same concentration of solutes as human blood, i.e., should be "isotonic.”
  • a composition of the present invention preferably does not contain phospholipids in any amount. More particularly, the invention preferably excludes the presence of colloidal structures such as liposomes, micelles, anisotropic liquid crystals, liquid crystalline mesophases, and complexes that include phospholipids or that are the direct result of the addition of phospholipids. Compare U.S. published patent application No. 2005/0244339.
  • the aerosol particles should be the correct size to deposit in the targeted region(s) of infection.
  • the median aerosol particle size for the present invention is preferably in the range of 1 to 5 ⁇ m.
  • the aerosolization characteristics of a pharmaceutical composition within the invention is determined primarily by the surfactant.
  • the inventors have discovered that a certain delivery system is surprisingly efficacious for delivering to the lungs a pharmaceutical composition solution of the invention that contains the surfactant tyloxapol ("tyloxapol-based pharmaceutical composition").
  • tyloxapol-based pharmaceutical composition contains the surfactant tyloxapol
  • This delivery system also should be efficacious when tyloxapol is replaced by another surfactant that induces a similar solution surface tension (see discussion below).
  • an "antimicrobial agent” in this context can be an antibiotic agent, an antiviral agent, or an antifungal agent, depending on the source of infection in the body.
  • the following enumeration of exemplary antimicrobial agents is not exclusive of those that are suitable for the present invention.
  • illustrative are the microorganisms mentioned that can be targeted by a surfactant-based antimicrobial solution for inhalation, pursuant to the invention.
  • An antibiotic agent treats gram negative bacteria, including Pseudomonas aeruginosa, and gram positive bacteria, including Streptococcus penumoniae and
  • Staphylococcs aureus Staphylococcs aureus.
  • Tobramycin is FDA-approved as an aerosolized antibiotic treatment for Pseudomonas aeruginosa.
  • Other antibiotic drugs that have some development in an aerosolized form include amakacin, ceftazidime, aztreonam, colistin, ciprofloxacin, azithromycin, pentamidine, and gentamicin.
  • Vancomycin, doxycycline, linezolid, meropenem, and tigecycline are antibiotic drugs that might also be successfully used in an inhaled form. Isoniazid, rifampin, and daptomycin should be utilized if the source of the infection is tuberculosis or other mycobacteria.
  • An antifungal agent targets a fungus such as Aspergillus fungi.
  • Amphotericin B or other appropriate antifungal agents should be used in the administered drug solution if the source of the infection is a fungus.
  • An antiviral agent acts against a virus such as influenza.
  • the present invention contemplates the use, in the manner described above, of zanamivir, oseltamivir, or any other antiviral agent that is appropriate for administration to the lungs.
  • the amount of agent in a pharmaceutical composition of the invention will vary, e.g., as a percentage by mass.
  • the tobramycin content in TOBI for instance, is approximately 6 % by mass, or 300 mg of tobramycin for each 5 ml of drug solution.
  • the tobramycin content of a drug solution can be up to about 10% by mass.
  • a formulation of the present invention may include any non-ionic surfactant that safely and effectively lowers the surface tension of an aerosolized drug solution, in keeping with the description above.
  • the amount of surfactant as a percentage by mass will vary among aerosolized drug solutions administered pursuant to the invention. For instance, when the surfactant in the drug solution is tyloxapol, the surfactant content should be between 0.01 and 1% by mass, or between about 0.5 and 50 mg of tyloxapol for each 5 ml of drug solution.
  • a formulation of the invention could include any one or more non-ionic surfactant selected from the group of: polysorbate 20, 40, 60, 65, 80, 81 and 85; sorbitan monopalmitate; sorbitan monostearate; sorbitan tristearate; sorbitan monooleate; and sorbitan trioleate.
  • non-ionic surfactant selected from the group of: polysorbate 20, 40, 60, 65, 80, 81 and 85; sorbitan monopalmitate; sorbitan monostearate; sorbitan tristearate; sorbitan monooleate; and sorbitan trioleate.
  • the optimal delivery system of the invention utilizes (i) a nebulizer that creates an aerosol only when the patient inhales (“breath-actuated nebulizer”), which maximizes the amount and rate of drug deposition in the body, with (ii) a "high- flow compressor,” which is a compressor that delivers gas at a rate greater than five liters per minute.
  • the high-flow compressor also delivers a pressure head of 40 psi to the breath-actuated nebulizer.
  • the breath-actuated nebulizer/high-flow compressor combination of the present invention comprises an AeroEclipse II Breath-Actuated Nebulizer in functional connection with a DeVilbiss 8650D high-flow compressor.
  • a delivery system of the invention also includes, typically integral with the nebulizer, (iii) a reservoir for storing a drug solution to be atomized by the nebulizer, and (iv) a conduit adapted for delivery of the aerosol to the user.
  • the reservoir can be a cartridge, tube, cup, or any container that stores fluid.
  • the conduit can be a hose, pipe, connector, tube, or any transport device that may be used to transport gas to a face mask, nozzle or any other device that delivers gas to the respiratory system.
  • This delivery system yields an aerosol with a median aerosol particle size that is effective for deposition of the drug solution on the target site in the lungs, especially the lung airways.
  • the delivery device combination can yield a median aerosol particle size between 1 and 5 ⁇ m, which is the particle size that is most effective for depositing in the lung branches.
  • the inventors produced a surfactant-based tobramycin solution for inhalation
  • SBTSI SBTSI
  • Each 10 ml of SBTSI comprised 0.5 ml of 20 mg/ml tyloxapol solution, 600 mg of tobramycin, and 43 mg of NaCl, with added water to reach 10 ml.
  • the solution did not include phospholipids.
  • the inventors In testing a delivery system for SBTSI, the inventors considered eleven aerosol delivery systems, each including a nebulizer and a compression source (see Table 1). The inventors employed a solution containing only the tyloxapol component of SBTSI, essentially to save the cost of repeated uses of the antibiotic, tobramycin. For testing purposes, this expediency was acceptable in principle because the surfactant component was the dominant factor affecting aerosolization.
  • Table 1 Nebulizer delivery systems included in study to determine optimal system for SBTSI.
  • the inventors also added a Technetium DTPA radioisotope tag to the tyloxapol solution.
  • the radioactivity associated with the Technetium DTPA allows for accurate measurement of liquid volume output when the aerosol is collected in collection filters. That is, the counts of radioactivity in a filter informs one of the percentage of volume output. Knowledge of the drug content per unit volume with the SBSTI solution then permits one to estimate drug output does.
  • liquid volume output of the tyloxapol solution is proportional to tobramycin output of the SBSTI solution (see below).
  • tagged tyloxapol is an accurate proxy for a surfactant-based antimicrobial solution for inhalation
  • the inventors used a Malvern Mastersizer S laser- diffraction instrument (Malvern Instruments, Ltd., Worcestershire, U.K.) to perform aerosol size comparisons on aerosolized SBTSI and aerosolized tyloxapol, each at identical concentrations. Both solutions were aerosolized by an AeroEclipse II nebulizer and an 8650D high-flow compressor.
  • Figure 2 shows the results verifying that the aerosol size for both solutions had similar median diameters and overall volume distributions.
  • the inventors applied these output rate and aerosol size measurements to an in vitro model, which estimated the deposited dose received from a nebulizer treatment.
  • the in vitro model was derived from past deposition studies of monosized aerosols and estimates total, pulmonary, and extrathoracic deposited dose.
  • the inventors previously employed radioisotope aerosol dose quantification tests to quantify the accuracy of the in vitro model. Testing of the in vitro model verified that it could accurately estimate the dose of medication delivered by a nebulizer. See Corcoran et al. (2006), supra, for further discussion of the in vitro model.
  • Figure 3 displays the results after the inventors used the in vitro model to predict pulmonary and total deposited tobramycin doses for 5 ml of drug solution administered from each of the eleven delivery systems tested.
  • Treatment time measured during output rate testing (see Figure 4), varied for the eleven delivery systems and should be taken into account when examining predicted doses.
  • the AeroEclipse II Breath-Actuated Nebulizer combined with the DeVilbiss 8650D high-flow compressor hereafter, "the second delivery system" had the highest predicted total and pulmonary delivery doses.
  • Figure 4 lists the results from the in vitro model for the eleven delivery systems in terms of predicted pulmonary delivery rate (predicted milligrams of tobramycin per minute). The second delivery system provided the greatest pulmonary dose delivery rate.
  • Figure 5 lists the predicted bronchial delivery rate based on measurements from the in vitro model. This metric is especially useful because the primary sites of infection resulting from cystic fibrosis are the large and small airways of the lungs. The second delivery system yielded the highest bronchial dose delivery rate.
  • the second delivery system was identified as the optimal delivery system for a tyloxapol-based antimicrobial solution for inhalation.
  • the inventors determined the aerosol volume distribution by respiratory tract region (see Figure 6). This histogram shows twenty-two particle size ranges. For each size range, the inventors predicted what percent of total aerosol volume comprised aerosol particles from the size range and what region of the respiratory tract on which particles from that size range were deposited.
  • a micropump nebulizer such as the Aerogen Pro, a product of Nektar/Aerogen (Sunnyvale, CA) is employed to produce a 4- to 5-micron median diameter aerosol, and tubing of decreasing diameter is used to deliver this aerosol through a 2 mm cannula tip.
  • the aerosol is driven through the tubing system by means of a small air compressor, such as the Pulmoaide, a product of Sunrise Medical (Somerset, PA).
  • the air is humidified and heated to 37 0 C via a humidification system such as the MR850, a product of Fisher & Paykel Healthcare (Laguna Hills, CA).
  • a flow meter placed upstream of the nebulizer is used to monitor and control air flow rate.
  • porcine gastric mucus porcine gastric mucus
  • non-CF HBEs human bronchial epithelial cell cultures from non-cystic fibrosis lungs
  • CF-HBEs human bronchial epithelial cell cultures from cystic fibrosis lungs
  • the PGM is mixed to a concentration of 50 mg/ml (95% saline) and loaded into 12 mm diameter filter inserts, e.g., the Corning-Costar Transwell Collagen T-cols (Acton, MA) to a depth of 4 mm.
  • the cannula is placed about 1 mm above the PGM surface, and aerosol is delivered at 0.3 LPM for 10 seconds.
  • epithelial cells are chemically detached from airway samples, cultured according to standard procedures, and seeded onto 12 mm transwell filters, where they are maintained at an air liquid interface until fully differentiated. Cultures are washed weekly, using applicable detergents, and also washed approximately 24 hours before testing.
  • the apical surface of the cells is hydrated with 100 ⁇ L of PBS solution, which then is suctioned off. Aerosol delivery is conducted onto the cells in a manner similar to that described for PGM surfaces.
  • Fluorescent probes are added to the solutions being tested, allowing for visualization of dispersion on the delivery surfaces.
  • Three probes are utilized: a hydrophilic saccharide such as Texas red dextran (Molecular Probes, Carlsbad, CA); a polystyrene sphere of the order of 0.1 micron in diameter; and a polystyrene sphere of the order of 1 micron in diameter, such as FluoSpheres (Molecular Probes, Carlsbad, CA).
  • Dispersion of the probes is tracked after delivery by means of a fluorescent dissecting microscope, e.g., the MVXlO MacroView, marketed by Olympus (Center Valley, PA).
  • Dispersion of the test solutions is compared to an isotonic saline control that contains similar probes and delivered in a similar manner.
  • Dispersion area is quantified using software tools such as MetaMorph, a product of Molecular Devices Corporation (Sunnyvale, CA). Approximately 8-fold increases in dispersion area vs. saline would be anticipated for a successful candidate solution on a PGM surface. Approximately 2-fold increases in dispersion area vs. saline would be anticipated for a successful candidate solution on both CF-HBE and non-CF HBE surfaces.

Abstract

Selon la présente invention, un tensioactif peut être ajouté, de manière sûre et efficace, à une solution médicamenteuse contenant un quelconque agent antimicrobien, tel qu'un antibiotique comme la tobramycine, qui convient à l'administration aux poumons par inhalation. Ainsi, lorsqu'une solution médicamenteuse aérosolisée contient un tensioactif, l'écoulement Marangoni amène les particules médicamenteuses, après leur dépôt dans les poumons, à se disperser sur une surface plus grande, ce qui garantit ainsi une plus grande efficacité antimicrobienne. Une solution qui contient, par exemple, un antibiotique et du tyloxapol ou un autre tensioactif donnant une tension superficielle similaire à la composition, est administrée de manière optimale par la combinaison fonctionnelle d'un nébuliseur actionné par l'inhalation et d'un compresseur à haut débit.
PCT/US2008/009931 2007-08-24 2008-08-21 Solution antimicrobienne à base de tensioactif, pour inhalation WO2009029192A1 (fr)

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AU2013259512B2 (en) * 2012-05-09 2018-01-25 Contrafect Corporation Bacteriophage lysin and antibiotic combinations against gram positive bacteria
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CN111491639A (zh) * 2017-09-20 2020-08-04 异位性医疗有限责任公司 用于治疗和改善呼吸道病况和粘膜炎症的组合物和方法
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